Microencapsulated 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles

ABSTRACT

The invention relates to a pharmaceutical composition comprising a biodegradable and biocompatible microparticle composition comprising a 1,2-benzazole of the formula ##STR1## and the pharmaceutically acceptable acid addition salts thereof, within a polymeric matrix.

This application is a continuation of application Ser. No. 08/808,261,filed Feb. 28, 1997, now U.S. Pat. No. 5,770,231 which is a continuationof application Ser. No. 08/154,403, filed Nov. 19, 1993 still pending.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to microencapsulated 1,2-benzazoles andtheir use in the treatment of warm blooded animals suffering from mentalillness More particularly, the present invention relates tomicroencapsulated 3-piperidinyl-substituted 1,2-benzisoxazoles and1,2-benzisothiazoles and their use in the treatment of mental patients.

2. Description of the Related Art

Strupczewski et al., in U.S. Pat. No. 4,352,811 and U.S. Pat. No.4,458,076, describe 3-piperidinyl-1,2-benzisoxazoles and3-piperidinyl-1,2-benzisothiazoles having antipsychotic and analgesicproperties.

Kennis et al., U.S. Pat. No. 4,804,663, disclose3-piperidinyl-1,2-benzisothiazoles and 3-piperidinyl-1,2-benzisoxazolesand their pharmaceutically acceptable acid addition salts that haveantipsychotic properties and are useful in the treatment of a variety ofcomplaints in which serotonin release is of predominant importance. Inparticular,3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one("Risperidone") is disclosed.

Janssen et al., U.S. Pat. No. 5,158,952,3-piperidinyl-1,2-benzisoxazoles having long-acting antipsychoticproperties and which are useful in the treatment of warm-blooded animalssuffering from psychotic diseases. In particular,3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one("9-hydroxy-Risperidone") is disclosed.

A number of methods are known by which compounds can be encapsulated inthe form of microparticles. In many of these processes, the material tobe encapsulated is dispersed in a solvent containing a wall formingmaterial. At a single stage of the process, solvent is removed from themicroparticles and thereafter the microparticle product is obtained.

An example of a conventional microencapsulation process andmicroparticles produced thereby is disclosed in U.S. Pat. No. 3,737,337,incorporated by reference herein, wherein a solution of a wall or shellforming polymeric material in a solvent is prepared. The solvent is onlypartially miscible in water. A solid or core material is dissolved ordispersed in the polymer-containing solution and, thereafter, thecore-material-containing solution is dispersed in an aqueous liquid thatis immiscible in the organic solvent in order to remove solvent from themicroparticles.

Another example of a process in which solvent is removed frommicroparticles containing a substance is disclosed in U.S. Pat. No.3,523,906. In this process a material to be encapsulated is emulsifiedin a solution of a polymeric material in a solvent that is immiscible inwater and then the emulsion is emulsified in an aqueous solutioncontaining a hydrophilic colloid Solvent removal from the microparticlesis then accomplished by evaporation and the product is obtained.

In still another process as shown in U.S. Pat. No. 3,691,090 organicsolvent is evaporated from a dispersion of microparticles in an aqueousmedium, preferably under reduced pressure.

Similarly, the disclosure of U.S. Pat. No. 3,891,570 shows a method inwhich solvent from a dispersion of microparticles in a polyhydricalcohol medium is evaporated from the microparticles by the applicationof heat or by subjecting the microparticles to reduced pressure.

Another example of a solvent removal process is shown in U.S. Pat. No.3,960,757.

Tice et al., in U.S. Pat. No. 4,389,330, describe the preparation ofmicroparticles containing an active agent--which may, inter alia, be apsychotherapeutic agent--by a method comprising: (a) dissolving ordispersing an active agent in a solvent and dissolving a wall formingmaterial in that solvent; (b) dispersing the solvent containing theactive agent and wall forming material in a continuous-phase processingmedium; (c) evaporating a portion of the solvent from the dispersion ofstep (b), thereby forming microparticles containing the active agent inthe suspension; and (d) extracting the remainder of the solvent from themicroparticles.

Tice et al., in U.S. Pat. No. 4,530,840, describe the preparation ofmicroparticles containing an anti-inflammatory active agent by a methodcomprising: (a) dissolving or dispersing an anti-inflammatory agent in asolvent and dissolving a biocompatible and biodegradable wall formingmaterial in that solvent; (b) dispersing the solvent containing theanti-inflammatory agent and wall forming material in a continuous-phaseprocessing medium; (c) evaporating a portion of the solvent from thedispersion of step (b), thereby forming microparticles containing theanti-inflammatory agent in the suspension; and (d) extracting theremainder of the solvent from the microparticles.

SUMMARY OF THE INVENTION

The present invention relates to microencapsulated 1,2-benzazoles andtheir use in the treatment of warm blooded animals suffering from mentaldisease. In a preferred embodiment, the invention relates to apharmaceutical composition designed for the controlled release of aneffective amount of a drug over an extended period of time, prepared inmicroparticle form. This composition comprises at least oneantipsychotic agent and at least one biocompatible, biodegradableencapsulating polymer.

More particularly, the present invention relates to a method of treatingwarm blooded animals suffering from psychotic disorders comprising theadministration thereto of a pharmaceutically effective amount of abiodegradable and biocompatible microparticle composition comprising a1,2-benzazole of the formula ##STR2## and the pharmaceuticallyacceptable acid addition salts thereof, wherein R is hydrogen or alkylof 1 to 6 carbon atoms;

R¹ and R² are independently selected from the group consisting ofhydrogen, halo, hydroxy, alkyloxy of 1 to 6 carbon atoms, and C alkyl of1 to 6 carbon atoms;

X is O or S;

Alk is C₁₋₄ alkanediyl; and

Q is a radical of formula ##STR3## wherein R³ is hydrogen or alkyl of 1to 6 carbon atoms;

Z is --S--, --CH₂ --, or --CR⁴ ═CR⁵ --; where R⁴ and R⁵ areindependently selected from the group consisting of hydrogen or alkyl of1 to 6 carbon atoms;

A is a bivalent radical --CH₂ --CH₂ --, --CH₂ --CH₂ --CH₂ -- or CR⁶ ═CR⁷--; where R⁶ and R⁷ are independently selected from the group consistingof hydrogen, halo, amino or alkyl of 1 to 6 carbon atoms; and

R⁸ is hydrogen or hydroxyl;

within a polymeric matrix.

In another aspect, the present invention relates to a pharmaceuticalcomposition comprising a biodegradable and biocompatible microparticlecomposition comprising a 1,2-benzazole of Formula I within a polymericmatrix.

In still another aspect, the present invention relates to a method ofinhibiting serotonergic or dopaminergic overstimulation in animalswherein said method comprises administration of a biodegradable andbiocompatible microparticle composition comprising a 1,2-benzazole ofFormula I within a polymeric matrix.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a laboratory set-up for carrying out a preferred processfor preparing the microparticles of the present invention:

FIG. 2 depicts a graph of in vitro dissolution data for risperidonemicroparticles of batch Prodex 3, both as produced and lyophilized.

FIG. 3 depicts a graph of in vitro dissolution data for risperidonemicroparticles of batch Prodex 2, both as produced and lyophilized.

FIG. 4 depicts a graph of accelerated in vitro dissolution data forrisperidone microparticles of batches Prodex 3 and Prodex 2.

FIG. 5 depicts a graph of mean (n=2) plasma concentration-time curvesfor the active moiety (sum of risperidone and 9-hydroxy risperidone)after single intramuscular administration to beagle dogs of risperidonedepot formulations at an approximate dose of 2.5 mg/kg. The period ofanti-emetic activity (in at least 2 out of 3 dogs) in the apomorphinevomiting test is given in the legend for each of the formulations. Anasterisk (*) indicates that the anti-emetic activity is interrupted inat least 2 out of 3 dogs at the beginning of the study. The broken lineindicates an approximate lowest minimum plasma concentration necessaryfor anti-emetic activity. The // sign indicates that for formulationProdex 2 no blood was sampled on days 14, 18, and 21.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is concerned with microencapsulated 1,2-benzazoleshaving the formula ##STR4## and the pharmaceutically acceptable acidaddition salts thereof, wherein R is hydrogen or alkyl of 1 to 6 carbonatoms;

R¹ and R² are independently selected from the group consisting ofhydrogen, halo, hydroxy, alkyloxy of 1 to 6 carbon atoms and alkyl of 1to 6 carbon atoms;

X is O or S;

Alk is alkanediyl of 1 to 4 carbon atoms; and

Q is a radical of formula ##STR5## wherein R³ is hydrogen or alkyl of 1to 6 carbon atoms;

Z is --S--, --CH₂ --, or --CR⁴ ═CR⁵ --; where R⁴ and R⁵ areindependently selected from the group consisting of hydrogen or alkyl of1 to 6 carbon atoms;

A is a bivalent radical --CH₂ --CH₂ --, --CH₂ --CH₂ --CH₂ -- or CR⁶ ═CR⁷--; where R⁶ and R⁷ are independently selected from the group consistingof hydrogen, halo, amino, or alkyl of 1 to 6 carbon atoms; and

R⁸ is hydrogen or hydroxyl.

In the foregoing definitions, the term "halo" is generic to fluoro,chloro, bromo, and iodo; "alkyl of 1 to 6 carbon atoms" is meant toinclude straight and branched chain saturated hydrocarbon radicalshaving from 1 to 6 carbon atoms, such as, for example, methyl, ethyl,propyl, butyl, pentyl, hexyl, and isomers thereof; "alkanediyl of 1 to 4carbon atoms" is meant to include bivalent straight or branched chainalkanediyl radicals having from 1 to 4 carbon atoms, such as, forexample, methylene, ethylene, propylene, butylene, and isomers thereof.

Preferred compounds within the invention are those wherein Q is aradical of formula (a) wherein R³ is alkyl of 1 to 6 carbon atoms and Ais a bivalent radical --CH₂ --CH₂ --, --CH₂ --CH₂ --CH₂ --, or --CR⁶═CR⁷ --, wherein R⁶ and R⁷ are independently selected from the groupconsisting of hydrogen and alkyl of 1 to 6 carbon atoms.

Particularly preferred compounds are those wherein Q is a radical offormula (a) wherein R³ is alkyl of 1 to 6 carbon atoms and A is abivalent radical --CH₂ --CH₂ --, --CH₂ --CH₂ --CH₂ --, or --CR⁶ ═CR⁷ --,wherein R⁶ and R⁷ are independently selected from the group consistingof hydrogen and alkyl of 1 to 6 carbon atoms, R is hydrogen, R¹ ishydrogen or halo, and R² is hydrogen, halo, hydroxy, or alkyloxy of 1 to6 carbon atoms.

More particularly preferred compounds are those wherein R is hydrogen,R¹ is hydrogen or halo, and R² is hydrogen, halo, hydroxy, or alkyloxyof 1 to 6 carbon atoms and Q is a radical of formula (a) wherein--Z--A-- is --CH₂ --CH₂ --CH₂ --CH₂ --, --S--CH₂ --CH₂ --, --S--(CH₂)₃--, --S--CR⁶ ═CR⁷ --, or --CH═CH--CR⁶ ═CR⁷ --, wherein R⁶ and R⁷ areindependently selected from the group consisting of hydrogen or methyl;

Especially preferred compounds are those compounds wherein R ishydrogen, R¹ is hydrogen, and R² is hydrogen, halo, hydroxy, or methoxyand Q is a radical of formula (a) wherein --Z--A-- is --CH₂ --CH₂ --CH₂--CH₂ --, --S--CH₂ --CH₂ --, --S--(CH₂)₃ --, --S--CR⁶ ═CR⁷ --, or--CH═CH--CR⁶ ═CR⁷ --, wherein R⁶ and R⁷ are independently selected fromthe group consisting of hydrogen or methyl.

The most preferred compounds are selected from the group consisting of3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one("Risperidone") and the pharmaceutically acceptable acid addition saltsthereof.

The compounds of formula (I) can generally be prepared by the methodsdescribed in U.S. Pat. No. 4,804,663, incorporated herein by reference.These methods comprise reacting an appropriate reactive ester of formula(II) with an appropriately substituted piperidine of formula (III). Inthe reactive ester (II), W represents a reactive ester moiety such as,for example, halo, e.g., chloro, bromo, or iodo, or a sulfonyloxy group,e.g. methylsulfonyloxy, (4-methylphenyl)sulfonyloxy, and the like.##STR6##

The reaction of (II) with (III) can conveniently be conducted in aninert organic solvent such as, for example, an aromatic hydrocarbon,e.g., benzene, toluene, xylene, and the like; a lower alkanol, e.g.,methanol, ethanol, propanol, butanol and isomers thereof; a ketone,e.g., acetone, 4-methyl-2-pentanone and the like; an ether, e.g.,1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like;N,N-dimethylformamide (DMF); N,N-dimethylacetamide (DMA); nitrobenzene;1-methyl-2-pyrrolidinone; and the like. The addition of an appropriatebase such as, for example, an alkali or an alkaline earth metalcarbonate, bicarbonate, hydroxide, alkoxide, or hydride, e.g., sodiumcarbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide,sodium methoxide, sodium hydride, and the like, or an organic base suchas, for example, a tertiary amine, e.g., N,N-diethylethanamine,N-(1-methylethyl)-2-propanamine, 4-ethylmorpholine, and the like can beused to neutralize the acid liberated during the course of the reaction.In some circumstances, the addition of an iodide salt, preferably analkali metal iodide, is appropriate. Moderately elevated temperaturescan be used to enhance the rate of the reaction.

The compounds of formula (I) can also be prepared following art-knownprocedures for preparing compounds containing radicals of formula Qwithin their structure.

The compounds of formula (I) wherein Q is a radical of formula (a), saidcompounds being represented by the formula (I-a), can be preparedfollowing art-known cyclizing procedures for preparing pyrimidin-4-ones,such as, for example, by reacting an amine of formula (VI) with acyclizing agent of formula (VII) or by cyclizing a reagent of formula(VIII) with an amine of formula (IX). ##STR7##

In the foregoing reaction schemes. L and L¹ each independently representan appropriate leaving group such as, for example, (C₁₋₆ alkyl)oxy,hydroxy, halo, amino, mono- and di(C₁₋₆ alkyl)amino, and the like.

Following the same cyclization procedure the compounds of formula (I-a)can also be prepared by cyclizing an intermediate of formula (IX) with areagent of formula (X). ##STR8##

The compounds of formula (I-a) wherein Z is S, said compounds beingrepresented by the formula (I-a-1), can also be prepared by cyclizing a2-mercaptopyrimidinone of formula (XI) with a reagent of formula (XII).##STR9##

In (XII), W¹ has the same meaning as previously described for W.

The compounds of formula (I-a-1) wherein A is ##STR10## said compoundsbeing represented by the formula (I-a-1-a), can also be prepared bycyclizing a 2-mercaptopyrimidinone of formula (XI) with a reagent offormula (XIII). ##STR11##

The cyclization reactions described above can be carried out asdescribed above.

The compounds of formula (I) have basic properties and, consequently,can be converted to their therapeutically active non-toxic acid additionsalt forms by treatment with appropriate acids, such as, for example,inorganic acids, such as hydrohalic acid, e.g., hydrochloric,hydrobromic, and the like; sulfuric acid, nitric acid, phosphoric acid,and the like; or organic acids, such as, for example, acetic, propanoic,hydroacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic,propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic,2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, toluenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic,4-amino-2-hydroxybenzoic, and the like acids. Conversely the salt formcan be converted by treatment with alkali into the free base form.

A number of intermediates and starting materials in the foregoingpreparations are known compounds that can be prepared according toart-known methodologies. For example, the intermediates of formula (III)and their preparations are described in U.S. Pat. Nos. 4,335,127;4,342,870; 4,443,451; and 4,485,107.

The intermediates of formula (III) can generally be derived from abenzoylpiperidine of formula ##STR12## wherein halo is preferablyfluoro, following art-known procedures, e.g., by reacting thebenzoylpiperidine (XIV) with hydroxylamine and cyclizing the thusobtained oxime ##STR13## following art known procedures, thus obtainingthe intermediate of formula (III) wherein X is O, said intermediatesbeing represented by the formula ##STR14##

The intermediates of formula (III) wherein X is S, said intermediatesbeing represented by the formula ##STR15## can be prepared following aprocedure analogous to that described in U.S. Pat. No. 4,458,076.

The compounds of formula (I) and the pharmaceutically acceptable acidaddition salts thereof are potent antagonists of a series ofneurotransmitters and, as a result, have useful pharmacologicalproperties. In particular, the compounds of formula (I) and theirpharmaceutically acceptable acid addition salts possess strong psychoticactivity and antiserotonin activity.

Janssen et al. (The Journal of Pharmacology and ExperimentalTherapeutics 244 (2):685-693 (1988)) made comparative studies ofrisperidone with ritanserin, a selective centrally acting serotonin-S₂antagonist and with haloperidol, a selective centrally actingdopamine-D₂ antagonist. They reported that risperidone, like ritanserin,showed activity in all tests related to serotonin-S₂ antagonism, but ateven lower doses. Like haloperidol, risperidone also showed activity inall tests related to dopamine-D₂ antagonism. They concluded that,qualitatively, risperidone is a mixed serotonin-dopamine antagonist.

Owing to their pharmacological activities, the compounds of formula (I)and their pharmaceutically acceptable acid addition salts are used inthe treatment of psychotic diseases and in the treatment of a variety ofcomplaints in which serotonin release is of predominant importance suchas, for example, in the blocking of serotonin-induced contractions ofbronchial tissues and of blood vessels, arteries as well as veins. Thesubject compounds are also useful as sedating, anxiolytic,anti-aggressive, anti-stress, muscular protectant, and cardiovascularprotectant agents and, consequently, are useful for protectingwarm-blooded animals, for example, in stress situations. Additionally,these compounds are useful for protection against endotoxine shocks andas antidiarrheals.

In view of the usefulness of the subject compounds in the treatment ofpsychotic diseases, it is evident that the present invention provides amethod of treating warm-blooded animals suffering from psychoticdisorders, said method comprising the systemic administration of apharmaceutically effective amount of a microencapsulated compound offormula (I) or a pharmaceutically acceptable acid addition salt thereofin admixture with a pharmaceutical carrier. In general, it iscontemplated that an effective amount of the compound, per se, would befrom 0.01 mg/kg to 4 mg/kg body weight, more preferably, from 0.04 mg/kgto 2 mg/kg body weight.

In order to provide a clear and consistent understanding of thespecification and claims, including the scope to be given such terms,the following definitions are provided.

By the term "administered" is intended any method of delivering the1,2-benzazole-containing microparticles of the invention to a warmblooded animal, such as, for example, parenteral (intravenous,intramuscular, or subcutaneous) administration.

By "microparticles" is meant solid particles that contain an activeagent, herein the 1,2-benzazole, either in solution or in crystallineform. The active agent is dispersed or dissolved within the polymer thatserves as the matrix of the particle.

The present invention concerns a method of treating mental illness inwarm blooded animals, preferably mammals, more preferably humans,(hereinafter, collectively referred to as "patients") that comprisesproviding to such patients biodegradable microparticles loaded with a1,2-benzazole, as described above. The method of the present inventionprovides advantages over methods known in the art, such as, inter alia,a biodegradable system, an injectable system that prevents the loss ofdose during treatment, the ability to mix microparticles containingdifferent drugs, and the ability to program release (multiphasic releasepatterns) to give faster or slower rates of drug release as needed.

The product of the present invention offers the advantage of durationsof action ranging from 7 to more than 200 days, depending upon the typeof microparticle selected. In a preferred embodiment, the microparticlesare designed to afford treatment to patients over a period of 30 to 60days. The duration of action can be controlled by manipulation of thepolymer composition, polymer:drug ratio, and microparticle size.

Another important advantage of the present invention is that practicallyall of the active agent is delivered to the patient because the polymerused in the method of the invention is biodegradable, thereby permittingall of the entrapped agent to be released into the patient.

A method for preparing the microparticles of the invention is alsodescribed in both U.S. Pat. No. 4,389,330 and U.S. Pat. No. 4,530,840,fully incorporated herein by reference.

The polymeric matrix material of the microparticles of the presentinvention is a biocompatible and biodegradable polymeric material. Theterm "biocompatible" is defined as a polymeric material that is nottoxic to the human body, is not carcinogenic, and does not significantlyinduce inflammation in body tissues. The matrix material should bebiodegradable in the sense that the polymeric material should degrade bybodily processes to products readily disposable by the body and shouldnot accumulate in the body. The products of the biodegradation shouldalso be biocompatible with the body in the same sense that the polymericmatrix is biocompatible with the body. Suitable examples of polymericmatrix materials include poly(glycolic acid), poly-D,L-lactic acid,poly-L-lactic acid, copolymers of the foregoing, poly(aliphaticcarboxylic acids), copolyoxalates, polycaprolactone, polydioxonone,poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone),polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, andnatural polymers including albumin, casein, and waxes, such as, glycerolmono- and distearate, and the like. The preferred polymer for use in thepractice of this invention is dl(polylactide-co-glycolide). It ispreferred that the molar ratio of lactide to glycolide in such acopolymer be in the range of from about 75:25 to 50:50.

In a preferred embodiment, administration of the 1,2-benzazoles topatients by the method of the invention is achieved by a singleadministration of the drug loaded microparticles, releasing the drug ina constant or pulsed manner into the patient and eliminating the needfor repetitive injections.

The formulation of the present invention contains an antipsychotic agentdispersed in a microparticle matrix material. The amount of agentincorporated in the microparticles usually ranges from about 1 wt % toabout 90 wt. %, preferably 30 to 50 wt. %, more preferably 35 to 40 wt.%. By weight % is meant parts of agent per total weight ofmicroparticle. For example, 10 wt. % agent would mean 10 parts agent and90 parts polymer by weight.

The molecular weight of the polymeric matrix material is of someimportance. The molecular weight should be high enough to permit theformation of satisfactory polymer coatings. i.e.. the polymer should bea good film former. Usually, a satisfactory molecular weight is in therange of 5,000 to 500,000 daltons, preferably about 150,000 daltons.However, since the properties of the film are also partially dependenton the particular polymeric material being used, it is very difficult tospecify an appropriate molecular weight range for all polymers. Themolecular weight of a polymer is also important from the point of viewof its influence upon the biodegradation rate of the polymer. For adiffusional mechanism of drug release, the polymer should remain intactuntil all of the drug is released form the microparticles and thendegrade. The drug can also be released from the microparticles as thepolymeric excipient bioerodes. By an appropriate selection of polymericmaterials a microparticle formulation can be made in which the resultingmicroparticles exhibit both diffusional release and biodegradationrelease properties. This is useful in affording multiphasic releasepatterns.

The microparticle product of the present invention can be prepared byany method capable of producing microparticles in a size rangeacceptable for use in an injectable composition. One preferred method ofpreparation is that described in U.S. Pat. No. 4,389,330. In this methodthe active agent is dissolved or dispersed in an appropriate solvent. Tothe agent-containing medium is added the polymeric matrix material in anamount relative to the active ingredient that provides a product havingthe desired loading of active agent. Optionally, all of the ingredientsof the microparticle product can be blended in the solvent mediumtogether.

Solvents for the agent and the polymeric matrix material that can beemployed in the practice of the present invention include organicsolvents, such as acetone; halogenated hydrocarbons, such as chloroform,methylene chloride, and the like; aromatic hydrocarbon compounds;halogenated aromatic hydrocarbon compounds: cyclic ethers; alcohols,such as, benzyl alcohol; ethyl acetate; and the like. A preferredsolvent for use in the practice of the present invention is a mixture ofbenzyl alcohol and ethyl acetate.

The mixture of ingredients in the solvent is emulsified in acontinuous-phase processing medium; the continuous-phase medium beingsuch that a dispersion of microdroplets containing the indicatedingredients is formed in the continuous-phase medium. Naturally, thecontinuous-phase processing medium and the organic phase must be largelyimmiscible. The continuous-phase processing medium most commonlyemployed is water, although nonaqueous media, such as, xylene, toluene,and synthetic and natural oils can be used. Usually, a surfactant isadded to the continuous-phase processing medium to prevent themicroparticles from agglomerating and to control the size of the solventmicrodroplets in the emulsion. A preferred surfactant-dispersing mediumcombination is a 0.1 to 10 wt. %, more preferably 0.5 to 2 wt. %solution of poly(vinyl alcohol) in water. The dispersion is formed bymechanical agitation of the mixed materials. An emulsion can also beformed by adding small drops of the active agent-wall forming materialsolution to the continuous phase processing medium. The temperatureduring the formation of the emulsion is not especially critical, but caninfluence the size and quality of the microparticles and the solubilityof the agent in the continuous phase. Of course, it is desirable to haveas little of the agent in the continuous phase as possible. Moreover,depending on the solvent and continuous-phase processing mediumemployed, the temperature must not be too low or the solvent andprocessing medium will solidify or become too viscous for practicalpurposes. On the other hand, it must not be so high that the processingmedium will evaporate or that the liquid processing medium will not bemaintained. Moreover, the temperature of the medium cannot be so highthat the stability of the particular active agent being incorporated inthe microparticles is adversely affected. Accordingly, the dispersionprocess can be conducted at any temperature that maintains stableoperating conditions, preferably about 20° C. to about 60° C., dependingupon the agent and excipient selected.

The dispersion formed is stable and from this dispersion the organicphase fluid can be partially removed in the first step of the solventremoval process. The solvent can easily be removed by common techniques,such as heating, the application of a reduced pressure, or a combinationof both. The temperature employed to evaporate solvent from themicrodroplets is not critical, but should not be so high as to degradethe agent employed in the preparation of a given microparticle or toevaporate solvent at a rate rapid enough to cause defects in the wallforming material. Generally, from 10 to 90%, preferably 40 to 60% of thesolvent is removed in the first solvent removal step.

After the first stage, the dispersed microparticles in the solventimmiscible fluid medium are isolated from the fluid medium by anyconvenient means of separation. Thus, for example, the fluid can bedecanted from the microparticles or the microparticle suspension can befiltered. Various other combinations of separation techniques can beused, if desired.

Following the isolation of the microparticles from the continuous-phaseprocessing medium, the remainder of the solvent in the microparticles isremoved by extraction. In this step, the microparticles can be suspendedin the same continuous-phase processing medium used in step one, with orwithout surfactant, or in another liquid. The extraction medium removesthe solvent from the microparticles, but does not dissolve them. Duringthe extraction, the extraction medium containing dissolved solvent mustbe removed and replaced with fresh extraction medium. This is best doneon a continual or continuous basis where the rate of extraction mediumreplenishment is critical. If the rate is too slow, agent crystals mayprotrude from the microparticles or grow in the extraction medium.Obviously, the rate of extraction medium replenishment for a givenprocess is a variable that can easily be determined at the time theprocess is performed and, therefore, no precise limits for the rate maybe predetermined. After the remainder of the solvent has been removed,the microparticles are dried by exposure to air or by other conventionaldrying techniques, such as, vacuum drying, drying over a desiccant, orthe like. This process is very efficient in encapsulating the agentsince core loadings of up to 80 wt. %, preferably up to 50 wt. % can beobtained.

A more preferred method of encapsulating the active agent to form thecontrolled release microparticles of the present invention involves theuse of static mixers, in the method disclosed by our co-worker, Paul F.Herbert, in co-pending U.S. patent application Ser. No. 08/154,409,filed of even date herewith.

Static or motionless mixers consist of a conduit or tube in which isreceived a number of static mixing elements. Static mixers providehomogeneous mixing in a relatively short length of conduit, and in arelatively short period of time. With static mixers, the fluid movesthrough the mixer, rather than some part of the mixer, such as a blade,moving through the fluid. A static mixer is more fully described in U.S.Pat. No. 4,511,258, which is incorporated herein by reference.

When using a static mixer to form an emulsion, a variety of factorsdetermine emulsion particle size. These factors include the density andviscosity of the various solutions or phases to be mixed, volume ratioof the phases, interfacial tension between the phases, static mixerparameters (conduit diameter; length of mixing element; number of mixingelements), and linear velocity through the static mixer. Temperature isa variable because it affects density, viscosity, and interfacialtension. The controlling variables are linear velocity, shear rate, andpressure drop per unit length of static mixer. Particularly, dropletsize decreases as linear velocity increases and droplet size increasesas pressure drop decreases. Droplets will reach an equilibrium sizeafter a fixed number of elements for a given flow rate. The higher theflow rate, the fewer elements needed. Because of these relationships,scaling from laboratory batch sizes to commercial batch sizes isreliable and accurate, and the same equipment can be used for laboratoryand commercial batch sizes.

In order to create microparticles containing an active agent, an organicphase and an aqueous phase are combined. The organic and aqueous phasesare largely or substantially immiscible, with the aqueous phaseconstituting the continuous phase of the emulsion. The organic phaseincludes an active agent as well as a wall forming polymer or polymericmatrix material. The organic phase can be prepared by dissolving anactive agent in an organic or other suitable solvent, or by forming adispersion or an emulsion containing the active agent. In the morepreferred process used in the practice of the present invention, theorganic phase and the aqueous phase are pumped so that the two phasesare simultaneously flowing through a static mixer, thereby forming anemulsion, which comprises microparticles containing the active agentencapsulated in the polymeric matrix material. The organic and aqueousphases are pumped through the static mixer into a large volume of quenchliquid. The quench liquid may be plain water, a water solution, or othersuitable liquid. Organic solvent may be removed from the microparticleswhile they are being washed or being stirred in the quench liquid. Afterthe microparticles are washed in a quench to extract or remove theorganic solvent, they are isolated, as through a sieve, and dried.

A laboratory set up for carrying out a static mixer process isillustrated in FIG. 1. An organic or oil phase 30 is prepared bydissolving and, optionally, heating an active agent and a polymericmatrix material or polymer in a stirred pot 32 on a hot plate. Howeverthe process of the present invention is not limited to preparing organicphase 30 by dissolving an active agent. Alternatively, organic phase 30may be prepared by dispersing an active agent in a solution containing apolymeric matrix material. In such a dispersion, the active agent isonly slightly soluble in organic phase 30. Alternatively, organic phase30 may be prepared by preparing an emulsion containing an active agentand a polymeric matrix material (double emulsion process). In the doubleemulsion process, a primary emulsion is prepared which contains anactive agent and a polymeric matrix material (organic phase 30). Theprimary emulsion may be a water-in-oil emulsion, an oil-in-wateremulsion, or any suitable emulsion. The primary emulsion (organic phase30) and an aqueous phase are then pumped through a static mixer to forma second emulsion which comprises microparticles containing the activeagent encapsulated in the polymeric matrix material.

Organic phase 30 is pumped out of stirred pot 32 by a magneticallydriven gear pump 34. The discharge of pump 34 feeds a "Y" connection 36.One branch 361 of "Y" connection 36 returns to pot 32 for recirculationflow. The other branch 362 feeds into an in-line static mixer 10.Aqueous or water phase 40 is prepared in like manner, with a stirred pot42, a magnetically driven gear pump 44, and a "Y" connection 46. Onebranch 461 of "Y" connection 46 returns to pot 42 for recirculationflow. The other branch 462 feeds into in-line static mixer 10. Organicphase 30 and aqueous phase 40 are substantially immiscible.

Branches 362 and 462 from each solution which feed in-line static mixer10 are joined by another "Y" connection 50 and feed through mixer inletline 51 into static mixer 10. Static mixer 10 discharges through mixeroutlet line 52 into wash tank 60. Silicone tubing and polypropylenefittings are used in the system illustrated in FIG. 1. Silicone tubinghaving 3/8 inch ID is used for all lines except mixer outlet line 52.Smaller diameter tubing (3/16 inch ID) is used for mixer outlet line 52to prevent collapse of the emulsion both in mixer outlet line 52 andupon entering wash tank 60.

In one embodiment of the process, pumps 34 and 44 are started inrecirculation mode and desired flow rates are set for organic phase 30and water phase 40. The flow rate of water phase 40) is preferablygreater than the flow rate of organic phase 30. However, the two flowrates may be substantially the same. The ratio of the flow rate of waterphase 40 to the flow rate of organic phase 30 is preferably in the rangeof 1:1 to 10:1. "Y" connection 46 is then switched so that water phase40 flows through branch 462 to static mixer 10. Once water phase 40fills mixer inlet line 51, static mixer 10, and mixer outlet line 52,"Y" connection 36 is switched so that organic phase 30 flows throughbranch 362 to static mixer 10. Organic phase 30 and aqueous phase 40 arenow flowing simultaneously through static mixer 10. When the desiredvolume of organic phase has been pumped to static mixer 10, "Y"connection 36 is switched to recirculation through branch 361. Waterphase 40 continues to flow for a short time to clean out any organicphase remaining in mixer inlet line 51, static mixer 10, and mixeroutlet line 52. "Y" connection 46 is then switched to recirculationthrough branch 461.

Organic phase 30 and aqueous phase 40 are mixed in static mixer 10 toform an emulsion. The emulsion formed comprises microparticlescontaining the active agent encapsulated in the polymeric matrixmaterial. The microparticles produced by the method of the presentinvention are usually of a spherical shape, although they may beirregularly shaped. The microparticles produced by the method of thepresent invention can vary in size, ranging from submicron to millimeterdiameters. In a preferred embodiment of the present invention, staticmixing elements 14 of static mixer 10 are selected so that the resultingmicroparticles range in size from 1 to 500 microns (μm), more preferably25 to 180 microns, whereby administration of the microparticles can becarried out with a standard gauge needle. The microparticles may bestirred in wash tank 60 which contains a quench liquid. Themicroparticles may be isolated from the quench liquid, such as by usinga sieve column. The microparticles may be dried using conventionaldrying techniques, and further size isolation may be done.

The active agent bearing microparticles are obtained and stored as a drymaterial. Prior to administration to a patient, the dry microparticlescan be suspended in an acceptable pharmaceutical liquid vehicle,preferably a 2.5 wt. % solution of carboxymethyl cellulose, whereuponthe suspension is injected into the desired portion of the body.

The microparticles can be mixed by size or by type so as to provide forthe delivery of active agent to the patient in a multiphasic mannerand/or in a manner that provides different agents to the patient atdifferent times, or a mixture of agents at the same time.

The following examples further describe the materials and methods usedin carrying out the invention. The examples are not intended to limitthe invention in any manner.

EXAMPLE 1

A mixture of 5.3 parts of3-(2-chloromethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-onemonohydrochloride, 4.4 parts of6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 8 parts of sodiumcarbonate, 0.1 part of potassium iodide, and 90 parts of DMF is stirredovernight at 80°-90° C. After cooling, the reaction mixture is pouredinto water. The product is filtered off and crystallized from a mixtureof DMF and 2-propanol. The product is filtered off and dried, yielding3.8 parts (46%) of3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;mp. 170.0° C.

EXAMPLE 2 Preparation of 35% Theoretically Loaded RisperidoneMicroparticles (Batch Prodex 2)

First, the aqueous phase (solution A) is prepared by weighing and mixing906.1 g 1% poly(vinyl alcohol), (Vinyl 205, Air Products and ChemicalInc., Allentown, Pa.), 29.7 g benzyl alcohol (J. T. Baker, Phillipsburg,N.J.) end 65.3 g ethyl acetate (Fisher Scientific, Fair Lawn, N.J.).Then the organic phase (solution B) is prepared by dissolving 29.3 g ofhigh viscosity 75:25 dl (polylactide-co-glycolide), (commerciallyavailable from Medisorb Technologies International, L. P., Cincinnati,Ohio) in 108.7 g ethyl acetate and 108.4 g benzyl alcohol. Once thepolymer is completely dissolved, 15.7 g risperidone base (JanssenPharmaceutica, Beerse, Belgium) is added and dissolved in the polymersolution. The exposure time of the dissolved risperidone with thepolymer is kept to a minimum (<10 minutes). Solutions A and B are thenpumped through a 1/4 inch diameter static mixer (Cole Parmer L04667-14)via a gear drive pump and head (Cole Parmer L07149-04, L07002-16) atflow rates of 198 and 24 ml/minute, respectively, into a quench composedof 55 liters of water for injection containing 1276.0 g of ethylacetate, 92.3 g (0.02 Molar) of anhydrous sodium bicarbonate, and 116.2g (0.02 Molar) of anhydrous sodium carbonate (Mallinckrodt SpecialtyChemicals, Paris, Ky.) at 11° C. The microparticles are allowed to stirin the first wash for 1.75 hours, then isolated by sieving with a25-micron sieve. The product retained by the sieve is transferred to a20-liter wash at 13° C. After stirring in the sieved wash for 2.25hours, the microparticles are isolated and size fractionated by sievingthrough a stainless steel sieve column composed of 25- and 180-micronmesh sizes. The microparticles are dried overnight, then collected andweighed.

EXAMPLE 3 Preparation of 40% Theoretically Loaded RisperidoneMicroparticles (Batch Prodex 3)

First, the aqueous phase (solution A) is prepared by weighing and mixing904.4 g 1% poly (vinyl alcohol), (Vinyl 205, Air Products and ChemicalInc., Allentown, Pa.), 30.1 g benzyl alcohol (J. T. Baker, Phillipsburg,N.J.) and 65.8 g ethyl acetate (Fisher Scientific, Fair Lawn, N.J.).Then the organic phase (solution B) is prepared by dissolving 27.1 g ofhigh viscosity 75:25 dl (polylactide-co-glycolide), (MedisorbTechnologies International, L. P., Cincinnati, Ohio) in 99.3 g ethylacetate and 99.1 g benzyl alcohol. Once the polymer is completelydissolved, 18.1 g risperidone base (Janssen Pharmaceutica, Beerse,Belgium) is added and dissolved in the polymer solution. The exposuretime of the dissolved risperidone with the polymer is kept to a minimum(<10 minutes). Solutions A and B are then pumped through a 1/4 inchdiameter static mixer (Cole Parmer L04667-14) via a gear drive pump andhead (Cole Parmer L07149-04, L07002-16) at flow rates of 198 and 24ml/minute, respectively, and into a quench composed of 55 liters ofwater for injection containing 1375.6 g of ethyl acetate, 92.4 g (0.02Molar) of anhydrous sodium bicarbonate, and 116.6 g (0.02 Molar) ofanhydrous sodium carbonate (Mallinckrodt Specialty Chemicals, Paris,Ky.) at 12° C. The microparticles are allowed to stir in the first washfor 2 hours, then isolated by sieving with a 25-micron sieve. Theproduct retained by the sieve is transferred to a 20-liter wash at 12°C. After stirring in the sieved wash for 3 hours, the microparticles areisolated and size fractionated by sieving through a stainless-steelsieve column composed of 25- and 180-micron mesh sizes. Themicroparticles are dried overnight, then collected and weighed.

EXAMPLE 4 Lyophilization and Gamma Irradiation of Microparticles fromBatches Prodex 2 and Prodex 3 (Samples Prodex 4A, Prodex 4B, and Prodex4C)

Microparticles from batches Prodex 2 and Prodex 3 were lyophilized. Themicroparticles were weighed into 5 cc serum vials. Then an aqueousvehicle composed of 0.75% CMC, 5% Mannitol, and 0.1% Tween 80 was addedto the vials. The microparticles were suspended in the vehicle byagitation, then quickly frozen in a dry ice/acetone bath. The vials werethen lyophilized in a pilot-scale lyophilizer (Dura Stop MicroprocessorControl, FTS Systems, Inc., Stone Ridge, N.Y.) employing a ramped 30° C.maximum temperature cycle for 50 hours. Samples Prodex 4A and Prodex 4Cwere lyophilized samples from Prodex 2 and Prodex 3, respectively.Sample Prodex 4B was lyophilized from Prodex 2 that had beensubsequently sterilized by 2.2 MRad gamma irradiation from a ⁶⁰ Cosource.

IN VITRO DISSOLUTION STUDIES

In vitro dissolution studies were conducted on Prodex 2, Prodex 3,Prodex 4A, Prodex 4B, and Prodex 4C. Real time and acceleratedmethodologies were used. The equipment consisted of a Hanson research6-cell USP paddle (Method II) dissolution apparatus interfaced with aspectrophotometer and data station. Receiving media were continuouslyrecirculated from each cell to flow cells inside the spectrophotometer(absorbance maximum of 236 nm).

The real time model measured the release rates of microparticles into areceiving medium consisting of 50 mM tris buffer at pH 7.4 at 37° C.Risperidone was found to have sufficient solubility (≧0.5 mg/ml) toallow in vitro experiments with this receiving medium. The amount ofrisperidone was kept below 20% of saturation to provide infinite sinkconditions. Data are shown in FIGS. 2 and 3.

An accelerated model was also developed. A receiving medium of 27.5 wt %ethanol was used. Results are shown in FIG. 4.

ANIMAL DOSING AND BLOOD SAMPLING

In vivo studies in dogs were conducted on product provided as drymicroparticles (Prodex 2, Prodex 3) and in lyophilized form (Prodex 4A,Prodex 4B, Prodex 4C). The dry microparticles were syringe-loaded andresuspended in the syringe with an injection vehicle comprised of 2.5 wt% carboxymethyl cellulose (CMC). The lyophilized samples (Prodex 4A,Prodex 4B, Prodex 4C) were reconstituted in WFI (water for injection)prior to injection.

Male and female dogs, weighing 11.6±2.3 kg, were divided into groups ofthree dogs each. The dogs were housed in groups of three and fedaccording to standard laboratory conditions.

The appropriate volumes of the respective depot formulations were dosedintramuscularly into the biceps femoralis of the left hind limb at thelevel of the thigh of the dogs at a dose of approximately 2.5 mg/kgrisperidone.

Blood samples (5 ml on EDTA) were taken from one of the jugular veins at0 (predose), 1, 5, and 24 hours after dosing and also on days 4, 7, 11,14, 18, 23, 25, 28, 32, 35, 39, 42, 46, 49, 53, and 56 at the time ofthe apomorphine vomiting test. The apomorphine test was described by P.A. J. Janssen and C. J. E. Niemegeers in Arzneim.-Forsch. (Drug Res.),9:765-767 (1959). If, during the course of the experiments, each of thethree dogs of a group no longer showed protection againstapomorphine-induced vomiting, blood sampling was discontinued. Bloodsamples were centrifuged at 3000 rpm for 10 min and plasma wasseparated. The plasma samples were stored at ≦20° C. until analysis.

Plasma samples were analyzed for risperidone (RISP) and for9-hydroxyrisperidone (9-OH RISP) using radioimmunoassay (RIA). For theplasma samples analyzed with RIA, two different RIA procedures wereused, one for unchanged risperidone and the other for the active moiety(sum of risperidone and 9-hydroxy-risperidone, not to be confused withthe term "active agent" used elsewhere herein). For the latter plasmasamples, the concentrations of 9-hydroxy-risperidone were calculated asthe difference between the concentrations of the active moiety and thoseof risperidone. The quantification limits for the RIA methods were 0.20ng/ml for risperidone and 0.50 ng/ml for the active moiety.

For each of the formulations, mean (±S.D., n=3) plasma concentrations ofrisperidone, 9-hydroxy-risperidone, and of the active moiety, werecalculated. Ratios of the plasma concentrations of 9-hydroxy-risperidoneto those of risperidone were calculated where possible. Peak plasmaconcentrations and peak times of risperidone, 9-hydroxy-risperidone, andtheir sum were determined by visual inspection of the data. AUC ("areaunder the curve") values of risperidone and 9-hydroxy-risperidone werecalculated between zero time and time using the trapezoidal rule. Thetime t is the last time point at which concentrations of risperidone or9-hydroxy-risperidone were higher than the limit of quantification in atleast 1 out of 3 dogs. For dogs belonging to the same formulation group,AUCs were calculated up to the same end-time t, using the value of thequantification limit, if one concentration was lower than thequantification limit. If two consecutive concentrations were lower thanthe quantification limit, the concentration of the earlier samplingpoint was set equal to the quantification limit, and the concentrationof the later sampling point was taken as zero. The AUCs were notextrapolated to infinity. The AUC of the active moiety was calculated asthe sum of the AUCs of risperidone and 9-hydroxy-risperidone.

Mean or median plasma concentrations and/or pharmacokinetic parametersof risperidone, 9-hydroxy-risperidone, and the active moiety forformulations Prodex 2/3/4A/4B/4C, are given in Table 1. Mean plasmaconcentration-time curves for formulations Prodex 2/3/4A/4B/4C are inFIG. 5. For each of the formulation groups, results are first discussedfor risperidone, then for 9-hydroxy-risperidone, and at last for theactive moiety. For the active moiety, plasma concentrations are relatedto the anti-emetic effect in the apomorphine vomiting test.

After administration of formulations Prodex 2 up to Prodex 4C, mean peakplasma levels of risperidone were low. They were attained at largelydifferent time points. The further release of risperidone from thedifferent formulations proceeded gradually and was long-lasting. Thisresulted in low plasma concentrations of both risperidone and itsmetabolite. Mean peak times for 9-hydroxy-risperidone all ranged from 26to 30 days. The plasma concentration-time profile of the active moietywas similar for formulations Prodex 2 up to Prodex 4C. At the beginningof the experiment, plasma concentrations of the active moiety showed apeak within 1 or 2 days, due to a rapid initial release of risperidone.The peak was followed by a decrease of the concentrations with a dip at5-8 days. From day 8 on, concentrations increased again until day 20,after which time they remained at a more or less constant level during aperiod of, on average, 15 days. During this period, for each of theformulations, concentrations of the active moiety showed a second peakand concentrations were higher than for the first peak. The anti-emeticactivity lasted 35 to 42 days for formulations Prodex 2, Prodex 4A, andProdex 4B. For formulation Prodex 4C, it lasted 49 days, but withoutinterruption in any of the dogs. The longest activity of formulationProdex 4C paralleled the highest C_(max), T_(max), and AUC_(0-t), forthe active moiety, in comparison with the other 4 formulations of thesame group.

The duration of action of these microparticle-based risperidoneformulations in the apomorphine-induced emesis test in dogs was alsostudied. Neuroleptics antagonized apomorphine-induced emesis by blockingdopamine D₂ receptors in the area postrema of the fourth ventricle. Thetest is generally used to predict the onset and duration ofantipsychotic action of neuroleptics in man (Janssen et al.,Arzneim.-Forsch./Drug Res. 15:1196-1206 (1965); Niemegeers et al., LifeSci. 24:2201-2216 (1979)). 9-OH-risperidone has a pharmacologicalprofile that is virtually identical to that of its parent compound.Parent compound and active metabolite constitute together the "activemoiety" that determines the biological activity of risperidone.

Apomorphine was administered subcutaneously at 0.31 mg/kg to the dogstwice a week, during the whole course of the experiment. The dogs wereobserved for vomiting during a 1-hour period after the administration ofapomorphine. Complete absence of emesis for 1 hour after apomorphinechallenge was considered to reflect significant anti-emetic activity.The duration of the anti-emetic action was defined as the time intervalduring which 2 out of 3 dogs were protected from emesis.

The formulations were injected in a volume of 0.5 ml into the bicepsfemoralis of one of the hind limbs at the level of the thigh. At severaltime intervals after the intramuscular injection, blood samples weretaken and, immediately thereafter, the dogs were challenged with a doseof apomorphine. Complete absence of emesis within 1 h after apomorphinechallenge (which is never observed in control animals; n>1000) wasconsidered to reflect significant antiemetic activity.

Table 2 indicates whether the dogs were protected (+) or not protected(-) from apomorphine-induced emesis at the various time intervals afterintramuscular injection of the depot formulations. All formulationsshowed an immediate onset of anti-emetic action.

                                      TABLE 1                                     __________________________________________________________________________    Mean (±S.D.; n = 3) or median plasma concentrations and mean               (±S.D.; n = 3) pharmacokinetic                                             parameters of risperidone, 9-hydroxy-risperidone, and their sum (=the         "active moiety") after                                                        intramuscular administration of risperidone depot formulations at 2.5         mg/kg to beagle dogs.                                                         __________________________________________________________________________             Prodex 2     Prodex 3    Prodex 4A                                   Time (days)                                                                            RISP  9-OH RISP                                                                            RISP  9-OH RISP                                                                           RISP  9-OH RISP                             __________________________________________________________________________    0        ≦0.20                                                                        ≦0.50                                                                         ≦0.20                                                                        ≦0.50                                                                        ≦0.20                                                                        ≦0.50                          0.042 (1 h)                                                                            8.36 ± 1.06                                                                      4.17 ± 1.71                                                                       21.4 ± 8.8                                                                       14.4 ± 9.1                                                                       3.25 ± 0.57                                                                      1.18 ± 0.50                        0.208 (5 h)                                                                            2.87 ± 0.20                                                                      7.34 ± 2.02                                                                       7.55 ± 3.38                                                                      27.4 ± 22.0                                                                      2.61 ± 0.60                                                                      5.13 ± 1.08                        1        1.25 ± 0.72                                                                      6.92 ± 3.88                                                                       2.90 ± 1.70                                                                      23.0 ± 17.8                                                                      1.13 ± 0.24                                                                      7.82 ± 3.55                        4        0.67 ± 0.6l                                                                      4.36 ± 3.32                                                                       1.22 ± 0.77                                                                      6.58 ± 3.07                                                                      0.74 ± 0.38                                                                      2.54 ± 1.20                        7        0.35* 1.65 ± 1.24                                                                       1.96 ± 1.70                                                                      8.79 ± 6.72                                                                      0.39* 1.90 ± 1.52                        11       0.41 ± 0.15                                                                      1.16 ± 0.35                                                                       1.52 ± 0.91                                                                      11.2 ± 11.7                                                                      2.40 ± 3.55                                                                      12.7 ± 20.2                        14       --**  --**   4.36 ± 1.99                                                                      29.4 ± 25.0                                                                      2.23 ± 1.19                                                                      12.6 ± 15.0                        18       --    --     6.33 ± 2.48                                                                      44.1 ± 35.4                                                                      4.28 ± 1.41                                                                      23.3 ± 12.5                        21       --    --     8.61 ± 2.25                                                                      44.8 ± 26.3                                                                      6.97 ± 1.57                                                                      27.1 ± 11.3                        25       6.79 ± 1.74                                                                      44.6 ± 13.6                                                                       9.08 ± 3.95                                                                      47.9 ± 19.5                                                                      6.03 ± 1.50                                                                      32.3 ± 2.8                         29       6.84 ± 3.19                                                                      46.0 ± 15.1                                                                       9.26 ± 5.27                                                                      54.2 ± 33.6                                                                      6.52 ± 1.40                                                                      40.2 ± 3.6                         32       4.97 ± 1.89                                                                      39.5 ± 36.6                                                                       5.60 ± 2.78                                                                      38.8 ± 25.2                                                                      3.81 ± 1.72                                                                      35.2 ± 16.3                        35       3.61 ± 1.84                                                                      25.8 ± 11.5                                                                       4.70 ± 3.39                                                                      28.4 ± 21.9                                                                      2.55 ± 1.31                                                                      22.1 ± 14.4                        39       1.44 ± 0.51                                                                      13.0 ± 7.1                                                                        2.01 ± 1.47                                                                      16.4 ± 9.6                                                                       1.13 ± 0.82                                                                      10.4 ± 6.4                         42       1.05 ± 0.45                                                                      7.73 ± 3.77                                                                       1.31 ± 0.79                                                                      10.7 ± 6.5                                                                       0.68* 6.08 ± 4.26                        46       ≦0.20*                                                                       2.94 ± 1.35                                                                       0.45* 5.55 ± 4.04                                                                      ≦0.20*                                                                       2.48 ± 1.81                        49       --    --     0.23* 2.13 ± 1.34                                                                      ≦0.20                                                                        1.23*                                 53       --    --     --    --    --    --                                    56       --    --     --    --    --    --                                    C.sub.max (ng/ml)                                                                      8.61 ± 1.41                                                                      61.0 ± 19.7                                                                       21.4 ± 8.8                                                                       56.3 ± 32.2                                                                      7.75 ± 0.78                                                                      43.9 6.6                              T.sub.max (days)                                                                       10 ± 17                                                                          29 ± 4                                                                            0.042 ±                                                                          26 ± 2                                                                           25 ± 4                                                                           30 ± 2                                                   0.000                                                   AUC.sub.0-t (ng · h/ml)                                                       3212 ± 914                                                                       21496 ± 4854                                                                      5048 ±                                                                           30632 ±                                                                          3280 ±                                                                           19632 ±                                                  2397  19866 576   8274                                  t(days)  46    46     49    49    46    49                                    __________________________________________________________________________             RISP + 9-OH RISP                                                                           RISP + 9-OH RISP                                                                          RISP + 9-OH RISP                            __________________________________________________________________________    C.sub.max (ng/ml)                                                                       67.3 ± 19.8                                                                            66.0 ± 37.0                                                                            49.6 ± 6.7                               T.sub.max (days)                                                                       29 ± 4    26 ± 2   30 ± 2                                   AUC.sub.0-t (ng · h/ml)                                                       24708 ± 5341                                                                            35680 ± 22261                                                                          22912 ± 8822                             __________________________________________________________________________                Prodex 4B        Prodex 4C                                        Time (days) RISP    9-OH RISP                                                                              RISP    9-OH RISP                                __________________________________________________________________________    0           ≦0.20                                                                          ≦0.50                                                                           ≦0.20                                                                          ≦0.50                             0.042 (1 h) 3.32 ± 0.75                                                                        2.53 ± 0.79                                                                         15.5 ± 5.2                                                                         3.32 ± 2.18                           0.208 (5 h) 1.52 ± 0.33                                                                        5.56 ± 2.43                                                                         15.1 ± 7.7                                                                         19.2 ± 6.2                            1           1.22 ± 0.58                                                                        7.10 ± 3.40                                                                         4.49 ± 1.04                                                                        25.0 ± 7.1                            4           0.58*   2.25 ± 1.00                                                                         2.00 ± 0.42                                                                        12.1 ± 2.5                            7           0.35*   1.78*    1.47 ± 0.29                                                                        7.96 ± 0.74                           11          0.53*   1.87*    3.23 ± 1.72                                                                        13.4 ± 4.6                            14          4.06 ± 3.47                                                                        22.1 ± 20.3                                                                         7.67 ± 4.54                                                                        30.9 ± 17.8                           18          1.41 ± 0.14                                                                        5.13 ± 0.85                                                                         8.15 ± 4.69                                                                        48.5 ± 34.5                           21          7.22 ± 4.98                                                                        27.1 ± 21.1                                                                         13.1 ± 9.4                                                                         69.3 ± 41.4                           25          5.39 ± 3.41                                                                        41.0 ± 29.7                                                                         8.37 ± 0.88                                                                        67.8 ± 28.0                           29          4.66 ± 1.47                                                                        31.1 ± 13.3                                                                         13.8 ± 5.2                                                                         77.9 ± 17.7                           32          3.50 ± 1.81                                                                        21.4 ± 9.8                                                                          10.3 ± 4.5                                                                         80.9 ± 51.3                           35          1.91 ± 0.71                                                                        14.9 ± 4.5                                                                          7.58 ± 3.49                                                                        61.4 ± 15.1                           39          0.67 ± 0.16                                                                        7.15 ± 2.47                                                                         3.90 ± 1.34                                                                        31.2 ± 10.7                           42          ≦0.20*                                                                         3.83 ± 0.40                                                                         2.97 ± 1.35                                                                        23.2 ± 13.7                           46          ≦0.20*                                                                         1.08 ± 0.53                                                                         0.68 ± 0.39                                                                        10.4 ± 6.3                            49          --      --       0.26*   6.04 ± 3.75                           53          --      --       ≦0.20*                                                                         2.98 ± 2.39                           56          --      --       ≦0.20*                                                                         1.89 ± 1.40                           C.sub.max (ng/ml)                                                                         7.71 ± 4.23                                                                        42.6 ± 27.3                                                                         16.3 ± 6.6                                                                         95.4 ± 41.7                           T.sub.max (days)                                                                          24 ± 5                                                                             26 ± 2                                                                              0.097 ± 0.096                                                                      30 ± 2                                AUC.sub.0-t (ng · h/ml)                                                          2648 ± 1199                                                                        15656 ± 8104                                                                        7424 ± 3018                                                                        46840 ± 19125                         t (days)    46      46       56      56                                       __________________________________________________________________________                RISP + 9-OH RISP RISP + 9-OH RISP                                 __________________________________________________________________________    C.sub.max (ng/ml)                                                                          48.5 ± 29.8  108 ± 44                                      T.sub.max (days)                                                                          26 ± 2        30 ± 2                                        AUC.sub.0-t (ng · h/ml)                                                          18311 ± 9222   54264 ± 22055                                __________________________________________________________________________     *Median value.                                                                **No blood sampling from day 14 until day 25 of the experiment, due to        absence of protection against apomorphineinduced vomiting. Concentrations     in italics indicate antiemetic activity in at least 2 out of 3 dogs.     

                                      TABLE 2                                     __________________________________________________________________________    Protection (+) or no protection (-) from apomorphine-induced emesis in        dogs at successive time intervals                                             after intramuscular administration of microparticle-based depot               formulations of the antipsychotic                                             risperidone at an approximate dose level of 2.5 mg/kg                         Form.                                                                              Prodex 2 Prodex 3 Prodex 4A                                                                              Prodex 4B                                                                              Prodex 4C                            __________________________________________________________________________    Dog  14.2                                                                             11.5                                                                             9.8                                                                              12.9                                                                             12.4                                                                             13.4                                                                             10.0                                                                             12.3                                                                             9.2                                                                              9.7                                                                              8.6                                                                              10.6                                                                             13.2                                                                             16.4                                                                             16.2                           Weight                                                                        (kg)                                                                          Volume                                                                             0.5.sup.3                                                                        0.5.sup.3                                                                        0.5.sup.3                                                                        0.5.sup.3                                                                        0.5.sup.3                                                                        0.5.sup.3                                                                        0.5.sup.3                                                                        0.5.sup.3                                                                        0.5.sup.3                                                                        0.5.sup.3                                                                        0.5.sup.3                                                                        0.5.sup.3                                                                        0.5.sup.3                                                                        0.5.sup.3                                                                        0.5.sup.3                      (ml/dog)                                                                      Dose 2.5                                                                              2.5                                                                              2.8                                                                              2.5                                                                              2.5                                                                              2.5                                                                              2.5                                                                              2.3                                                                              2.6                                                                              2.5                                                                              2.5                                                                              2.6                                                                              2.4                                                                              2.4                                                                              2.5                            (mg/kg)                                                                       Route                                                                              im im im im im im im im im im im im im im im                             1 h  +  +  -  +  +  +  +  +  +  -  +  +  +  +  +                              5 h  +  +  +  +  +  +  +  +  +  +  -  +  +  +  +                              1 d  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +                              4 d  -  -  +  +  -  +  +  +  -  -  -  +  +  +  +                              7 d  -  -  -  -  +  +  -  -  -  -  -  +  +  +  +                              11 d -  -  -  +  +  +  +  +  -  -  -  +  +  +  +                              14 d          +  +  +  +  +  -  -  -  +  +  +  +                              18 d          +  +  +  +  +  +  +  +  +  +  +  +                              21 d          +  +  +  +  +  +  +  +  +  +  +  +                              25 d +  +  +  +  +  +  +  +  +  +  +  +  +  +  +                              29 d +  +  +  +  +  +  +  +  +  +  +  +  +  +  +                              32 d +  +  +  +  +  +  +  +  +  +  +  +  +  +  +                              35 d +  +  +  +  +  +  +  +  +  +  +  +  +  +  +                              39 d -  +  +  +  -  +  +  +  -  -  -  -  +  +  +                              42 d -  -  -  +  -  +  +  -  -  -  -  -  +  +  -                              46 d -  -  -  +  -  -  -  -  -  -  -  -  +  +  -                              49 d Stop     -  -  -  -  -  -  Stop     +  +  -                              53 d          Stop     Stop              -  +  -                              56 d                                     -  -  -                                                                       Stop                                 __________________________________________________________________________     .sup.3 Injection volume: 0.5 ml/dog; the concentration of the                 microparticles was adapted to the body weight.                           

What is claimed is:
 1. A sustained-release microparticle comprising: a1,2-benzazole of the formula ##STR16## and the pharmaceuticallyacceptable acid addition salts thereof, wherein R is hydrogen or alkylof 1 to 6 carbon atoms;R¹ and R² are independently selected from thegroup consisting of hydrogen, halo, hydroxy, alkyloxy of 1 to 6 carbonatoms, and C alkyl of 1 to 6 carbon atoms; X is O or S; Alk is C₁₋₄alkanediyl; and Q is a radical of formula ##STR17## wherein R³ ishydrogen or alkyl of 1 to 6 carbon atoms; Z is --S--, --CH₂ --, or --CR⁴═CR⁵ --; where R⁴ and R⁵ are independently selected from the groupconsisting of hydrogen or alkyl of 1 to 6 carbon atoms; A is a bivalentradical --CH₂ --CH₂ --, --CH₂ --CH₂ --CH₂ -- or CR⁶ ═CR⁷ --;where R⁶ andR⁷ are independently selected from the group consisting of hydrogen,halo, amino or alkyl of 1 to 6 carbon atoms; and R⁸ is hydrogen orhydroxyl; and a biodegradable and biocompatible polymeric matrix.
 2. Thesustained-release microparticle of claim 1, wherein the biodegradableand biocompatible polymeric matrix is selected from the group consistingof poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid,copolymers of the foregoing, poly(aliphatic carboxylic acids),copolyoxalates, polycaprolactone, polydioxonone, poly(ortho carbonates),poly(acetals), poly(lactic acid-caprolactone), polyorthoesters,poly(glycolic acid-caprolactone), polyanhydrides, albumin, casein, andwaxes.
 3. The sustained-release microparticle of claim 1, wherein said1,2-benzazole comprises 1 to 90 wt. % of the microparticle.
 4. Thesustained-release microparticle of claim 1, wherein said 1,2-benzazolecomprises about 35 to 40 wt. % of the microparticle.
 5. Thesustained-release microparticle of claim 1, wherein the microparticleranges in size from 1 to 500 microns.
 6. The sustained-releasemicroparticle of claim 1, wherein the microparticle ranges in size from25 to 180 microns.
 7. The sustained-release microparticle of claim 1,wherein the microparticle is formulated in a liquid injection vehicle.8. The sustained-release microparticle of claim 7, wherein said liquidinjection vehicle is selected from the group consisting ofA.physiological saline solution and B. an aqueous solution ofcarboxymethyl cellulose with a surfactant.
 9. The sustained-releasemicroparticle of claim 1, wherein the microparticle is administered byintramuscular injection.
 10. The sustained-release microparticle ofclaim 1, wherein the microparticle is administered by subcutaneousinjection.
 11. The sustained-release microparticle of claim 1, whereinthe 1,2-benzazole is selected from the group consisting of3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneand the pharmaceutically acceptable acid addition salts thereof.
 12. Thesustained-release microparticle of claim 1, wherein the 1,2-benzazole isselected from the group consisting of3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneand the pharmaceutically acceptable acid addition salts thereof.